Loss of inhibitory control over appetitively motivated behavior, sometimes manifested as `bingeing', is a phenotype present in multiple psychiatric conditions. It is widely assumed that bingeing emerges from the dysregulated function of frontal-executive control mechanisms that govern subcortical motivation systems; nevertheless, specific neuropharmacological mechanisms and circuit connections are not clearly understood. One clue derives from the fact that opiate antagonist drugs are among the only pharmacotherapies with some efficacy in improving inhibitory control across a wide variety of psychiatric disorders with binge features. Hence, opioid actions within frontal circuits could be a crucial substrate underlying binge-type pathologies. To date, however, opioid effects in frontal cortex have been almost completely overlooked. In the previous funding period, we discovered that -opioid receptor (OR) stimulation in rat ventromedial prefrontal cortex (PFC) - an area analogous to those showing abnormal responses in a variety of disorders with binge features - engenders robust non-homeostatic feeding and hyperactivity, increased food motivation in a progressive-ratio task, and robust `impulsivity-like' impairments in a PFC-sensitive task of inhibitory control. These effects were not reproduced by a wide array of monoamine receptor agonists or antagonists, demonstrating unique actions of ORs relative to other PFC modulatory systems. Furthermore, dual-site drug microinfusion studies revealed that PFC OR signaling engages appetitive drive via feeding/arousal circuits in the lateral-perifornical hypothalamic region (LH-PeF), including the hypocretin/orexin system, while concurrently causing activation of an AMPA-coded PFC?nucleus accumbens shell (AcbSh) circuit that limits food motivation. Finally, we found that repeated episodes of sweetened-fat `gorging' sensitize AcbSh GABA systems, potentially blunting the effect the PFC?AcbSh `limiter circuit'. Based on these findings, we propose a novel network model stating that loss of control over appetitive behavior occurs when subcortical systems are driven by excessive PFC-OR signaling, and/or when there is an imbalance in the PFC?LH-PeF (`appetitive-driver') and PFC?AcbSh (`appetitive limiter') pathways. Moreover, we propose that palatable food gorging causes neuroplastic changes in AcbSh amino-acid (glutamate, GABA) systems that blunt incoming PFC signals, curbing the influence of the `limiter circuit', thereby allowing appetitive behavior to go unchecked. In this way, the neuroadaptations caused by intense reward-driven feeding could engage a vicious cycle, leading to further binge-like behavior. We will test this working hypothesis with a combination of classic pharmacology experiments and studies using virally introduced Designer Receptors Exclusively Activated by Designer Drugs (DREADDs). These engineered receptors permit the activation of G-proteins with a synthetic ligand; thus, neuronal activity can be modulated within specific populations of virally transduced neurons. Using a dual-virus approach, we will target DREADD expression to PFC neurons specifically projecting either to the AcbSh or to the hypothalamus, and selectively manipulate these tagged neurons in rats performing operant tasks of food motivation and inhibitory control. Furthermore, using classic pharmacology + DREADD experiments, we will test the hypothesis that palatable-food bingeing desensitizes vmPFC?AcbSh `limiter circuit' and perhaps amplifies the vmPFC?hypothalamus `appetitive-driver' circuit. Using receptor antagonists, we will examine the role of endogenous -opioid and hypocretin/orexin transmission in mediating PFC-driven food motivation and impulsivity. Finally, we will explore possible gender differences in PFC-OR control of food motivation and food impulsivity.